The transport of non-ferrous divalent metals, such as zinc, copper, nickel and cadmium, in serum is under investigation. The long-term objective of this research is to achieve a more complete understanding of the physiological and pathological mechanisms of metal and organic ion transport and homeostasis, especially in the perinatal period, and thus make possible improved clinical diagnosis and therapy. The 3.8 S alpha 2-histidine-rich glycoprotein (HRG) of serum binds divalent metal ions, like cadmium, copper and zinc with high affinity. In addition, the serum concentration of HRG declines in women during pregnancy to a level that is only 60% of that of healthy adult women. These observations suggest that HRG may have an important role in the homeostasis or transport of metal ions in serum and in providing essential metal nutrients to the fetus. Three basic approaches are used. First, we are determining the concentrations of HRG in serum in pregnancy and in a variety of disease states. Second, we are characterizing the physical-chemical properties of HRG with emphasis on its interactions with metals and the residues of the proteins that contribute to this function. Third, we are developing an animal model to enable us to pursue metabolic studies of HRG in pregnancy and in aberrant states of metal metabolism. Immunological methods are being developed for the specific identification and quantitation of protein-metal complexes in serum.